The present invention relates to agents which can prevent the formation of, or dissociate or destabilize an MSF-A-HIF1α protein complex and, more particularly, to the use of such agents in treating cancer.
Hypoxia-inducible factors (HIFs) are transcription factors involved in the transcription activation of several genes including, angiogenic factors (e.g., VEGF and FLT1), glucose transporters (Glut-1 and Glut-3), and glycolytic enzymes which are involved in the production of ATP in the absence of O2 (for overview see Semenza G L. 2003; Nat. Rev. Cancer 3: 721-732; Paul S A, Simons J W, Mabjeesh N J. 2004; J. Cell Physiol. 200: 20-30). HIF transcription factors are composed of two subunits, HIF-α and HIF-β. While the HIF-β is constitutively expressed, the expression of HIF-α is regulated by the level of oxygen. Thus, in the presence of normal oxygen tension (i.e., normoxia), HIF-1α is hydroxylated at the two critical proline residues (402 and 564 of GenBank Accession No. NP—001521) by members of the prolyl hydroxylase protein (PHD) family (PHD-1, -2, and -3). Hydroxylated-HIF-1α can then bind the von Hippel-Lindau (VHL) tumor suppressor protein, which recruits the E3 ubiquitin-ligase complex to targeting the HIF-α protein to proteasomal degradation. However, since oxygen is the rate-limiting co-factor of PHD enzymes, at low oxygen tension (i.e., hypoxia conditions), the prolyl hydroxylases are unable to hydroxylate HIF-α. As a result, no VHL interaction occurs and the E3 ubiquitin-ligase complex is unable to target HIF-1α to proteasomal degradation, resulting in stabilization of HIF. Stabilized HIF-1α can then form a heterodimer with the HIF-1β, which interacts with the basic helix-loop-helix domain of the hypoxia response element (HRE) in target genes.
In addition, hydroxylation of an asparagine residue in the C-terminal transactivation domain (TAD) of HIF-α (at position 803) by the factor inhibiting HIF-1 (FIH-1) negatively regulates transcriptional activity of HIF by preventing its interaction with p300 and CBP transactivators.
Elevated levels of HIF-1α protein are found in the majority of solid tumors and cancer metastases in the areas of profound hypoxia (Quintero M, Mackenzie N, Brennan P A. 2004; Eur. J. Surg. Oncol. 30: 465-8). In addition, a number of oncogenes such as AKT, Src, and oncogenic Ras were found to induce HIF expression (Li J, et al., 2004; Cancer Res. 64: 94-101). Moreover, p53 and Hsp90 were found to positively and negatively regulate HIF-1α degradation, respectively, i.e., while under normoxia P53 promotes HIF-1α degradation (Choi K S et al., 2003; J. Biochem. Mol. Biol. 36: 120-7), Hsp90 has a protective role in VHL-independent degradation of HIF-1α (Isaacs J S et al., J. Biol. Chem. 2004; 279: 16128-35). In addition, in many cases, the major reason for the failure of cancer therapy is the resistance of hypoxic cancer cells to both chemotherapy and radiation (Escuin D et al., 2004; Cancer Biol Ther. 3(7). Epub ahead of print). Thus, HIF-1α has been recognized as a possible target for anti cancer therapy (Welsh S J and Powis G. 2003; Curr Cancer Drug Targets. 3(6): 391-405; Macpherson G R and Figg W D, 2004; Cancer Biol. Ther. 3(6). Epub ahead of print).
Several agents capable of downregulating HIF-1 have been identified as potential anti-cancer agents including FK228, a histone deacetylase (HDAC) inhibitor (Mie Lee Y et al., 2003. Biochem. Biophys. Res. Commun 300: 241-6), PX-478, a small-molecule HIF-1 inhibitor, (Macpherson G R, Figg W D. 2004. Cancer Biol. Ther. 3(6) Epub ahead of print) and Bisphenol A, an environmental endocrine-disrupting chemical (Kubo T et al., 2004; Biochem. Biophys. Res. Commun 318(4): 1006-11). However, although desired, the mechanisms leading to up- or down-regulation of HIFs in cancerous tumors are not yet clear, thus, limiting the use of HIF-1 inhibitors/suppressors as anti cancer agents.
While reducing the present invention to practice, the present inventor has uncovered that MSF-A, a myeloid/lymphoid leukemia septin-like fusion protein A, regulates HIF-1α activity and thus contributing to cancer progression.